Cancer Immunology

Table of contents

Introduction

Cancer immunology is a rapidly growing field focusing on how the immune system can be harnessed to fight cancer.
The immune system can detect and eliminate abnormal cells, including cancer cells, through a complex network of cells and molecules.
However, cancer cells have developed multiple strategies to evade the immune system.
Cancer immunology aims to understand these interactions and find ways to overcome immune evasion to improve treatment outcomes.
Immunotherapy has become an important part of cancer treatment, with therapies designed to boost the body’s natural defenses or to directly target cancer cells.

History

Early Ideas (1890s)
- William Coley, often referred to as the “father of cancer immunotherapy,” observed that some cancer patients who developed bacterial infections experienced regression of their tumors.
- He developed a treatment called “Coley’s toxins,” which involved injecting patients with killed bacteria to stimulate the immune system.
Mid-20th Century
- In the 1950s, scientists discovered that the immune system could detect cancer cells.
- However, it was unclear how the immune system differentiated between normal and cancer cells.
- This era was marked by the discovery of tumor antigens, but it wasn’t until the 1980s that the immune system’s role in cancer was better understood.
1980s-1990s
- Researchers discovered the concept of immune checkpoints, which are mechanisms by which the immune system is regulated to prevent autoimmunity.
- This understanding set the stage for developing immune checkpoint inhibitors, which could release the “brakes” on immune responses.
Modern Era (2000s-Present)
- The approval of immune checkpoint inhibitors like ipilimumab (against CTLA-4) in 2011 for melanoma and nivolumab (against PD-1) in 2014 marked a turning point in immunotherapy.
- This opened the door for immune-based treatments for a wide range of cancers.

Cancer Cells

Cancer cells differ from normal cells in a few fundamental ways:

Uncontrolled Proliferation: Cancer cells have mutations in their DNA that allow them to escape normal regulatory mechanisms, causing uncontrolled cell division.
Avoiding Apoptosis: Cancer cells can evade programmed cell death, a natural mechanism that would otherwise eliminate abnormal cells.
Angiogenesis: Cancer cells secrete factors that stimulate the formation of new blood vessels (angiogenesis), ensuring the tumor gets enough nutrients and oxygen.
Metastasis: Cancer cells can invade neighboring tissues and spread to distant organs via the bloodstream or lymphatic system.

These characteristics allow cancer cells to survive and grow uncontrollably, and they often alter their surface proteins, making it harder for the immune system to detect them.

Classification of Cancer Cells

Cancers are classified based on the type of tissue or organ from which they arise:

Carcinomas: The most common type of cancer, arising from epithelial cells. Examples include lung cancer, breast cancer, and colon cancer.
Sarcomas: Cancers that develop in connective tissues, such as bone, muscle, and fat. Examples include osteosarcoma and liposarcoma.
Leukemias: Cancers of the blood and bone marrow that lead to the overproduction of abnormal blood cells. Examples include leukemia and lymphoma.
Lymphomas: Cancers of the immune system, specifically lymphocytes (white blood cell). Examples include Hodgkin lymphoma and non-Hodgkin lymphoma.
Melanomas: Cancers that arise from melanocytes, the pigment-producing cells in the skin. Melanoma is the deadliest form of skin cancer.

Classifications based on molecular markers have become increasingly important, as different tumors may have different genetic mutations, influencing their response to treatments.

Cancer Antigens

Tumor antigens are molecules present in cancer cells that the immune system can recognize. There are two main types:

Tumor-Specific Antigens (TSAs)
- These antigens are unique to tumor cells and not found in normal cells.
- They arise due to genetic mutations that alter proteins.
- TSAs are usually highly specific to the individual tumor and are typically recognized as foreign by the immune system.
- They can be a target for immunotherapies like cancer vaccines or CAR-T cell therapy.
Tumor-Associated Antigens (TAAs)
- These are antigens that are found in both normal cells and tumor cells but are expressed at much higher levels in the latter.
- They include proteins like HER2/neu (associated with breast cancer), PSA (prostate cancer), and MAGE family proteins.
- These antigens can be targeted for immune therapy, though because they are also expressed in normal tissues, targeting TAAs may lead to side effects.

Immunoediting

Immunoediting describes how the immune system interacts with tumors over time, leading to changes in both the immune system and the tumor. This process has three phases:

Elimination: The immune system detects and eliminates most tumor cells. This is the ideal phase, where the immune system destroys the tumor early on, preventing cancer from developing.
Equilibrium: Some cancer cells survive and are kept in check by the immune system in a dormant state. These cells are under constant immune surveillance but do not proliferate aggressively.
Escape: Cancer cells accumulate additional mutations that allow them to evade immune detection. This phase is characterized by tumor progression and metastasis.

In the escape phase, cancer cells may alter their surface antigens, secrete immunosuppressive molecules (like TGF-β), or recruit immune cells that inhibit the immune response (like regulatory T cells).

Immunomodulation Methods

Immunomodulation refers to modifying or enhancing the immune response to fight cancer. Several approaches are currently used or being developed:

Immune Checkpoint Inhibitors: These drugs block immune checkpoint proteins such as PD-1, PD-L1, and CTLA-4. Normally, these checkpoints act as “brakes” to prevent the immune system from attacking normal tissues. Cancer cells often exploit these checkpoints to evade immune detection. Checkpoint inhibitors release these brakes, allowing the immune system to attack the tumor.
- PD-1/PD-L1 inhibitors: Drugs like nivolumab and pembrolizumab target PD-1 on T cells or PD-L1 on tumor cells to restore T cell activity.
- CTLA-4 inhibitors: Ipilimumab is an example of a CTLA-4 inhibitor that stimulates T cells to attack cancer cells.
Cancer Vaccines: Cancer vaccines are designed to stimulate the immune system to target cancer-specific antigens.
- Preventive Vaccines: These include vaccines like the HPV vaccine, which can prevent cancers related to HPV infection, including cervical cancer.
- Therapeutic Vaccines: These vaccines are given to cancer patients to stimulate an immune response against existing tumors. An example is sipuleucel-T for prostate cancer.
Adoptive Cell Therapy
- Involves isolating immune cells (typically T cells), expanding and modifying them (e.g., inserting chimeric antigen receptors, or CARs), and reintroducing them into the patient.
- CAR-T cell therapy has been especially successful in treating certain types of blood cancers (e.g., acute lymphoblastic leukemia and non-Hodgkin lymphoma).
Monoclonal Antibodies
- These are antibodies engineered to target specific tumor antigens.
- For example, trastuzumab (Herceptin) is a monoclonal antibody that targets the HER2 receptor in breast cancer.
Cytokine Therapy
- This approach uses cytokines (signalling molecules) like interleukin-2 (IL-2) and interferons to boost the immune system’s ability to fight cancer.

Relationship to Chemotherapy

Chemotherapy, primarily designed to kill rapidly dividing cancer cells, affects the immune system. The relationship between chemotherapy and immunology can be described in several ways:

Immunogenic Cell Death
- Some chemotherapy drugs can cause cells to undergo a type of death that is “immunogenic,” meaning it triggers an immune response.
- For example, drugs like oxaliplatin induce ICD by causing cancer cells to release signals that attract immune cells.
Immune Suppression
- Chemotherapy can suppress the immune system by depleting certain immune cells, particularly white blood cells, which can make patients more susceptible to infections and limit the effectiveness of immunotherapies.
Combination Therapy
- Combining chemotherapy with immunotherapy has gained attention because it may offer synergistic benefits.
- While chemotherapy can make the tumor more “visible” to the immune system by causing ICD, immune checkpoint inhibitors can help the immune system respond more effectively to cancer.